Tailored Therapy: Saving Bel's Life

By Mike O'Kelly Photography by Seth Dixon

St. Jude spearheads a study that personalizes treatment for patients who inherit a high-risk gene variation.

Six-year-old Belinda “Bel” Mandy Goh Zhi Xuan gave her parents a friendly wave and flashed a bright smile as they snapped photos before she began her first day of school in January 2015. Pulling a sparkling pink backpack on wheels, Bel bounced into her first-grade classroom in Sarawak, a Malaysian state on the island of Borneo.

It was a snapshot moment for parents to treasure forever—a moment that inspired the work of researchers half-a-world away at St. Jude Children’s Research Hospital in Memphis, Tennessee.

At age 4, Bel was found to have acute lymphoblastic leukemia (ALL). She began receiving treatment at the National University Hospital in Singapore, an institution with a long history of collaboration with St. Jude. But her white blood cell count plummeted and she developed infections after treatment with mercaptopurine, an essential chemotherapy drug. The standard 50-milligram dose was reduced to 15 milligrams, and eventually she was taken off the drug for a brief time. Unfortunately, the side effects returned each time she resumed treatment, even at these lower doses.

Bel’s painful cycle of toxicity prompted her physician, Allen Yeoh, MD, who trained at St. Jude, to reach out to Jun J. Yang, PhD, of St. JudePharmaceutical Sciences. The two began studying the cause of Bel’s unusual response to this drug in hopes of finding a potential solution for other children like Bel.

It’s gratifying to know that the research we do can make a positive difference in the lives of these young patients.

Jun J. Yang, PhD

A medical mystery

For decades, St. Jude has been at the forefront of research in pharmacogenetics—the study of how genes affect a person’s response to drugs. Most patients have no problem metabolizing mercaptopurine, which is part of a larger class of drugs known as thiopurines. However, previous St. Jude research found that patients with limited activity in an enzyme known as TPMT had problems breaking down thiopurines. That results in a toxic buildup of the medicine in the body, causing infections, anemia and bleeding.

Bel underwent pharmacogenetics testing for the TPMT enzyme, but her levels of the enzyme were normal. So what was preventing her body from metabolizing the drug?

Yang and a team of international collaborators found the answer. His laboratory led research that included 270 children with ALL enrolled in clinical trials in Singapore, Guatemala and Japan.

Up to 25 percent of leukemia patients with East Asian ancestry in the trial had one of four variations that were found in a gene called NUDT15.

Because everyone has a unique set of DNA, each person has small differences in the genes that code for enzymes. The NUDT15 gene tells the body how to break down thiopurines. Similar to earlier TPMT research, the study revealed that four variations in the NUDT15 gene reduce the body’s ability to metabolize the medicine. The variations were also common in other Asian and Hispanic populations.

Jun J. Yang, PhD (at left), Takaya Moriyama, MD, PhD, and their colleagues discovered that children such as Bel Xuan who inherit certain versions of the NUDT15 gene are extremely sensitive to an important family of anti-cancer drugs. A simple genetic test can help doctors choose the best dose of drug for these children.

Dialing down the dose

The research showed that the NUDT15 enzyme balances thiopurine activity by breaking down the excess drug and therefore helping prevent toxicity and other complications. Scientists learned the NUDT15 variations caused a 74-to-100 percent loss of the gene’s function. That led to a toxic buildup of the drug at standard doses.

Further testing revealed that Bel had the NUDT15 variant, which meant her treatment could now be tailored to avoid a severe drug reaction. Eventually, her physicians dialed down her dosage of mercaptopurine to a tolerable 2 milligram dose.

“She is back in school and doing great,” Yang says. “It’s gratifying to know that the research we do can make a positive difference in the lives of these young patients.”

Genetics and treatment

According to Yang, the study’s findings will help clinicians develop more effective, personalized thiopurine therapy. Clinical evidence has shown that patients of Asian ancestry often cannot tolerate mercaptopurine dosages commonly used in the United States and Europe.

“In the future, we hope patients like Bel will not have to endure these severe side effects, and that we can reduce the toxicity dramatically by knowing a patient’s genetics in the beginning and using that information to guide treatment,” Yang says.